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Gadd45a deletion aggravates hematopoietic stem cell dysfunction in ATM-deficient mice

Chen, Yulin ; Yang, Runan ; Guo, Peng ; Ju, Zhenyu

Protein & cell, 2014, Vol.5 (1), p.80-89 [Periódico revisado por pares]

Beijing: Higher Education Press

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Título:
Gadd45a deletion aggravates hematopoietic stem cell dysfunction in ATM-deficient mice
Autor: Chen, Yulin ; Yang, Runan ; Guo, Peng ; Ju, Zhenyu
Assuntos: Animals ; Ataxia Telangiectasia Mutated Proteins - genetics ; ATM ; a蛋白 ; B-Lymphocytes - pathology ; Biochemistry ; Biomedical and Life Sciences ; Cell Biology ; Cell Cycle Proteins - genetics ; Cell Proliferation ; Cyclin-Dependent Kinase Inhibitor p21 - metabolism ; Developmental Biology ; DNA Damage ; DNA损伤 ; Gadd45 ; Gadd45a ; Hematopoietic Stem Cell Transplantation ; hematopoietic stem cells ; Hematopoietic Stem Cells - metabolism ; Hematopoietic Stem Cells - pathology ; Human Genetics ; Leukemia - genetics ; Leukemia - pathology ; Life Sciences ; Lymphoma - genetics ; Lymphoma - pathology ; Mice, Knockout ; Neoplasm Metastasis ; Nuclear Proteins - genetics ; Protein Science ; Research Article ; Stem Cells ; T-Lymphocytes - pathology ; Tumor Suppressor Protein p53 - metabolism ; 功能障碍 ; 小鼠 ; 缺陷 ; 造血干细胞
É parte de: Protein & cell, 2014, Vol.5 (1), p.80-89
Notas: Gadd45a, ATM, hematopoietic stem cellsDNA damage
Ataxia telangiectasia mutated （ATM） kinase plays an essential role in the maintenance of genomic stability. ATM-deficient （ATM-/-） mice exhibit hematopoietic stem cell （HSC） dysfunction and a high incidence of lym- phoma. Gadd45a controls cell cycle arrest, apoptosis and DNA repair, and is involved in the ATM-p53 mediated DNA damage response. However, the role of Gadd45a in regulating the functionality of ATM-/- HSCs is unknown. Here we report that Gadd45a deletion did not rescue the defects of T-cells and B-cells development in ATM-/- mice. Instead, ATM and Gadd45a double knockout （ATM-/- Gadd45a-/-） HSCs exhibited an aggravated defect in long-term self-renewal capacity compared to ATM-/- HSCs in HSC transplantation experiments. Fur- ther experiments revealed that the aggravated defect of ATM-/- Gadd45a-/- HSCs was due to a reduction of cell proliferation, associated with an accumulation of DNA damage and subsequent activation of DNA damage response including an up-regulation of p53-p21 signal- ing pathway. Additionally, ATM-/- Gadd45a-/- mice showed an increased incidence of hematopoietic malignancies, as well as an increased rate of metastasis than ATM-/- mice. In conclusion, Gadd45a deletion aggravated the DNA damage accumulation, which sub- sequently resulted in a further impaired self-renewal capacity and an increased malignant transformation in ATM-/- HSCs.
11-5886/Q
Gadd45a
Document accepted on :2013-12-25
ATM
Document received on :2013-12-19
hematopoietic stem cells
DNA damage
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Descrição: Ataxia telangiectasia mutated （ATM） kinase plays an essential role in the maintenance of genomic stability. ATM-deficient （ATM-/-） mice exhibit hematopoietic stem cell （HSC） dysfunction and a high incidence of lym- phoma. Gadd45a controls cell cycle arrest, apoptosis and DNA repair, and is involved in the ATM-p53 mediated DNA damage response. However, the role of Gadd45a in regulating the functionality of ATM-/- HSCs is unknown. Here we report that Gadd45a deletion did not rescue the defects of T-cells and B-cells development in ATM-/- mice. Instead, ATM and Gadd45a double knockout （ATM-/- Gadd45a-/-） HSCs exhibited an aggravated defect in long-term self-renewal capacity compared to ATM-/- HSCs in HSC transplantation experiments. Fur- ther experiments revealed that the aggravated defect of ATM-/- Gadd45a-/- HSCs was due to a reduction of cell proliferation, associated with an accumulation of DNA damage and subsequent activation of DNA damage response including an up-regulation of p53-p21 signal- ing pathway. Additionally, ATM-/- Gadd45a-/- mice showed an increased incidence of hematopoietic malignancies, as well as an increased rate of metastasis than ATM-/- mice. In conclusion, Gadd45a deletion aggravated the DNA damage accumulation, which sub- sequently resulted in a further impaired self-renewal capacity and an increased malignant transformation in ATM-/- HSCs.
Editor: Beijing: Higher Education Press
Idioma: Inglês

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Gadd45a deletion aggravates hematopoietic stem cell dysfunction in ATM-deficient mice

Chen, Yulin ; Yang, Runan ; Guo, Peng ; Ju, Zhenyu

Beijing: Higher Education Press

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